Because of the difficulties of low sensitivity for anticancer agents and giving sufficient dose because of poor liver function, chemotherapy may not play a central role for treatment of hepatocellular carcinoma (HCC) patients, especially those with liver cirrhosis. However, chemotherapy must be one of the important possibilities of multimodal treatment for advanced HCC, for which hepatic resection, percutaneous ablation, transcatheter arterial embolization and other general therapies would not be effective or even possible. Also, intra-arterial perfusion chemotherapy is a common therapy for HCC and it is not difficult to maintain; but the effective rate is not sufficient. Recently, the combination therapy of s.c. interferon (IFN)-α and intra-arterial 5-fluorouracil (5-FU) showed an outstandingly effective rate for intractable HCC (with portal vein thrombosis). In addition,recent preclinical and clinical studies have revealed that the mechanism of combination therapy may concern direct antitumor effects (through cell-cycle arrest and induction of apoptosis) and indirect actions (through immunocompetent cells and anti-angiogenic effect). For the further advance of HCC treatment and prognosis, this therapy might be a promising treatment modality and is expected to develop. In this review, we summarize recent clinical and preclinical data regarding IFN-α and 5-FU combination therapy and discuss the further prospects of this therapy.